Fatty acids have been proposed as excipients in pharmaceutical compositions of unconjugated drug molecules. For example, U.S. Pat. No. 4,338,306 to Kitao et al. proposes pharmaceutical compositions for rectal administration of insulin. The pharmaceutical compositions include insulin and fatty acids having 8 to 14 carbon atoms and nontoxic salts thereof.
U.S. Pat. No. 5,658,878 to Bäckström et al. proposes a therapeutic preparation for inhalation that includes insulin and a substance which enhances the absorption of insulin in the lower respiratory tract. The enhancer can be a sodium salt of a saturated fatty acid of carbon chain length 10 (i.e., sodium caprate), 12 (sodium laurate), or 14 (sodium myristate). Potassium and lysine salts of capric acid are also proposed. Bäckström et al. notes that if the carbon chain length is shorter than about 10, the surface activity of the surfactant may be too low, and if the chain length is longer than about 14, decreased solubility of the fatty acid in water limits its usefulness. As an alternative to the proposed fatty acid enhancers, Bäckström et al. proposes the use of the following bile salts—sodium ursodeoxycholate, sodium taurocholate, sodium glycocholate, and sodium taurodihydrofusidate.
U.S. Pat. No. 6,200,602 to Watts et al. proposes drug delivery compositions for colonic delivery of insulin. The drug delivery compositions include insulin, an absorption promoter which (a) includes a mixture of fatty acids having 6 to 16 carbon atoms or a salt thereof and a dispersing agent, or (b) comprises a mixture of mono/diglycerides of medium chain fatty acids and a dispersing agent, and a coating to prevent the release of the insulin and absorption promoter until the tablet, capsule or pellet reaches the proximal colon.
Bile salts have been proposed as excipients in pharmaceutical compositions of unconjugated drug molecules. For example, U.S. Pat. No. 4,579,730 to Kidron et al. proposes pharmaceutical compositions for the oral administration of insulin. The pharmaceutical compositions include insulin, a bile acid or alkali metal salt thereof, the bile acid being selected from the group consisting of cholic acid, chenodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, glycocholic acid, glycochenocholic acid, 3β-hydroxy-12-ketocholic acid, 12α-3β-dihydrocholic acid, and ursodesoxycholic acid, and a protease inhibitor. The composition is provided with an enterocoating to assure passage through the stomach and release in the intestine.
U.S. Pat. No. 5,283,236 to Chiou proposes compositions for systemic delivery of insulin through the eyes where the drug passes into the nasolacrimal duct and becomes absorbed into circulation. The composition includes insulin and an enhancing agent. The enhancing agents proposed include, either alone or in combination, surfactants such as polyoxyethylene ethers of fatty acids, and bile salts and acids such as cholic acid, deoxycholic acid, glycocholic acid, glycodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, sodium cholate, sodium glycocholate, glycocholate, sodium deoxycholate, sodium taurodeoxycholate, chenodeoxycholic acid, and ursodeoxycholic acid. The enhancer is present in a concentration ranging from 0.1% to 5% (w/v).
U.S. Pat. No. 5,853,748 to New proposes enteric-coated compositions for oral administration of insulin. The composition includes insulin, a bile salt or bile acid, and carbonate or bicarbonate ions, which are used to adjust the pH of the gut to a pH of from 7.5 to 9.
In at least one instance, a mixture of a low detergent bile salt, such as ursodeoxycholate, and a C12 to C24 fatty acid, such as linoleic or oleic acid, has been proposed as an excipient in a pharmaceutical composition of orally active pharmaceutically active agents that need to be protected from the acidic and enzymatic environment of the stomach and for which the gastrointestinal mucosa should be protected from adverse effects of the drug. The described pharmaceutical composition is proposed to be particularly suitable for the non-steroidal anti-inflammatory drug, indomethacin.
It is desirable to provide pharmaceutical compositions for administration of drug-oligomer conjugates.